EP3536342A1 - Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers - Google Patents

Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers Download PDF

Info

Publication number
EP3536342A1
EP3536342A1 EP19155349.4A EP19155349A EP3536342A1 EP 3536342 A1 EP3536342 A1 EP 3536342A1 EP 19155349 A EP19155349 A EP 19155349A EP 3536342 A1 EP3536342 A1 EP 3536342A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
tmprss2
inhibitor
antibody
influenza virus
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19155349.4A
Other languages
English (en)
French (fr)
Inventor
Lisa Purcell Ngambo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of EP3536342A1 publication Critical patent/EP3536342A1/de
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to the treatment and prophylaxis of influenza virus infection. More specifically, the invention relates to the use of type II transmembrane serine protease inhibitors (TTSPs), such as anti-TMPRSS2 antibodies, to treat or prevent influenza virus infection in a subject.
  • TTSPs type II transmembrane serine protease inhibitors
  • the influenza virus infection process is initiated by the attachment of virus particles (virions) to target cells followed by fusion of the viral envelope with the target cell membrane. Viral attachment and cell fusion are mediated by the viral envelope protein hemagglutinin (HA).
  • HA consists of two subunits: HA1 which mediates the attachment step, and HA2 which mediates the fusion step.
  • HA is initially synthesized as an inactive precursor (HA0) in which HA1 and HA2 are connected by a protease-sensitive linker sequence. Cleavage of the linker by host cell proteases produces the functional HA1 and HA2 subunits.
  • cleavage of HA is an essential, host-mediated step in the influenza virus infection process, host cell proteases that mediate the activation of HA have been proposed as therapeutic targets against influenza infection. (See, e.g., Bottcher et al., (2006) J. Virol. 80:9896-9898 ).
  • TTSPs such as transmembrane protease serine S1 member 2 (TMPRSS2), TMPRSS4 and human airway trypsin-like protease (HAT).
  • TMPRSS2 transmembrane protease serine S1 member 2
  • HAT human airway trypsin-like protease
  • TTSP e.g ., an anti-TMPRSS2 antibody
  • the present invention addresses the aforementioned need in the art by providing methods for treating or preventing influenza virus infection.
  • the methods of the present invention comprise administering to a subject in need thereof a pharmaceutical composition comprising a type II transmembrane serine protease (TTSP) inhibitor.
  • TTSP type II transmembrane serine protease
  • the TTSP is an inhibitor of TMPRSS2.
  • Exemplary TMPRSS2 inhibitors that can be used in the context of the present invention include, e.g., small molecule protease inhibitors, peptide inhibitors, nucleic acid-based inhibitors, and antibodies or antigen-binding fragments of antibodies that specifically bind TMPRSS2.
  • a TMPRSS2 inhibitor is administered to a subject in need thereof, wherein the TMPRSS2 inhibitor is specific for TMPRSS2 and/or is the only TTSP inhibitor administered to the subject.
  • an anti-TMPRSS2 antibody is administered to a subject, wherein the anti-TMPRSS2 antibody only inhibits the activity of TMPRSS2, and no other TTSP inhibitor (e.g ., TMPRSS4 inhibitor, HAT inhibitor, etc.) is administered to the subject.
  • the present invention also includes embodiments wherein a second therapeutic agent is administered to the subject in combination with the TTSP inhibitor.
  • a second therapeutic agent is administered to the subject in combination with the TTSP inhibitor.
  • the present invention includes methods in which an anti-TMPRSS2 antibody is administered to a subject in combination with one or more antiviral agents, and/or in combination with an anti-influenza antibody.
  • the present invention provides methods for treating or preventing influenza virus infection.
  • the expression “treating influenza virus infection” means improving, reducing, or alleviating at least one symptom or biological consequence of influenza virus infection in a mammal, and/or reducing or decreasing influenza virus titer, load, replication or proliferation in a mammal following exposure to an influenza virus.
  • the expression “treating influenza virus infection” also includes shortening the time period during which a subject exhibits at least one symptom or biological consequence of influenza virus infection after being infected by influenza virus.
  • Methods for treating influenza virus infection comprise administering a pharmaceutical composition of the present invention to a subject after the subject is infected with an influenza virus and/or after the subject exhibits or is diagnosed with one or more symptoms or biological consequences of influenza virus infection.
  • the expression "preventing influenza virus infection” means preventing at least one symptom or biological consequence of influenza virus infection in a mammal, and/or inhibiting or attenuating the extent to which influenza virus is capable of entering, spreading, and/or propagating within/among cells of an animal body.
  • the expression "preventing influenza virus infection” also includes decreasing the susceptibility of a subject to at least one symptom or biological consequence of influenza virus infection.
  • Methods for preventing influenza virus infection comprise administering a pharmaceutical composition of the present invention to a subject before the subject is infected with an influenza virus and/or before the subject exhibits one or more symptoms or biological consequences of influenza virus infection.
  • Methods for preventing influenza virus infection may include administering a pharmaceutical composition of the present invention to a subject at a particular time period or season of the year (e.g., during the 1-2 month period just prior to the time at which peak numbers of individuals are typically found to experience influenza virus infection), or before the subject travels to or is exposed to an environment with high frequencies of influenza virus infection, and/or before the subject is exposed to other subjects who are infected with influenza virus.
  • symptom or biological consequence of influenza virus infection includes one or more of nasal congestion, sinus congestion, runny nose, sneezing, body (muscle) ache, head ache, chills, fever, cough, sore throat, fatigue, ear ache, or a diagnostic indicator of influenza virus infection. Diagnostic indicators of influenza virus infection include, e .
  • a subject who tests positive for influenza virus infection by a diagnostic assay is considered a subject exhibiting a "symptom or biological consequence of influenza virus infection.”
  • TMPRSS2 transmembrane serine protease
  • TMPRSS2 knock-out mice that were challenged with influenza virus did not show an increase in influenza-positive alveolar macrophages, neutrophils or epithelial cells in the lungs, whereas the frequency of these influenza-infected cell types was significantly increase in the lungs of wild-type mice after influenza virus challenge.
  • TMPRSS2 knock-out mice also exhibited complete survival and weight gain/maintenance characteristics following influenza virus challenge.
  • the present invention also provides methods for preventing or reducing the accumulation of influenza-infected alveolar macrophages, influenza-infected neutrophils and/or influenza-infected epithelial cells in the lungs of a subject that has been exposed to or challenged with influenza virus, wherein the method comprises administering to the subject a pharmaceutical composition comprising a type II transmembrane serine protease (TTSP) inhibitor.
  • TTSP transmembrane serine protease
  • the methods of the present invention can be used to treat or prevent influenza virus infection in any subject for whom such treatment or prevention would be beneficial.
  • the subject can be a human or non-human animal (e.g., equine, canine, bovine, feline, ovine, porcine, avian, etc.).
  • the subject to be treated includes any individual who exhibits at least one symptom or biological consequence of influenza virus infection (as that phrase is defined herein).
  • methods of prevention the subject can be any individual who may be at risk of being exposed to influenza virus or who has the potential of coming into contact with another individual who is infected by influenza virus.
  • the methods of the present invention may be particularly useful for treating or preventing influenza virus infection in a patient group selected from elderly subjects, cancer patients (e.g., individuals undergoing chemotherapy, radiation or other anti-cancer therapeutic regimen), and immuno-incompetent or immunocompromised individuals.
  • a patient group selected from elderly subjects, cancer patients (e.g., individuals undergoing chemotherapy, radiation or other anti-cancer therapeutic regimen), and immuno-incompetent or immunocompromised individuals.
  • subjects who are unable to adequately respond to influenza vaccination or other anti-viral therapies, or who are intolerant to conventional therapies e . g ., individuals with egg allergies who are precluded from influenza vaccination
  • conventional therapies e . g ., individuals with egg allergies who are precluded from influenza vaccination
  • the methods of the present invention comprise administering a pharmaceutical composition comprising a type II transmembrane serine protease (TTSP) inhibitor to a subject.
  • TTSPs include transmembrane protease serine S1 member 2 (TMPRSS2), transmembrane protease serine S1 member 4 (TMPRSS4), and human airway trypsin-like protease (HAT).
  • the TTSP inhibitor can be a small molecule protease inhibitor, a nucleic acid-based inhibitor (e.g ., siRNA, ribozyme, antisense construct, etc.), antigen-binding protein (e.g ., antibody or antigen-binding fragment thereof), or a blocking peptide/peptide inhibitor.
  • the TTSP inhibitor may function by inhibiting or reducing the ability of a TTSP to proteolytically cleave hemagglutinin precursor protein (HAO) into the HA1 and HA2 subunits.
  • HEO hemagglutinin precursor protein
  • the TTSP inhibitor is a TMPRSS2 inhibitor such as an antibody or antigen-binding fragment thereof that specifically binds TMPRSS2 and inhibits the proteolytic activity of TMPRSS2.
  • the antibody or antigen-binding fragment thereof may inhibit or reduce the ability of TMPRSS2 to proteolytically cleave hemagglutinin precursor protein (HAO) into the HA1 and HA2 subunits.
  • HEO hemagglutinin precursor protein
  • An antibody is deemed to inhibit the protease activity of a TTSP (e.g ., TMPRSS2) if the antibody, when mixed with the TTSP, reduces the proteolytic activity of the TTSP by at least 25% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) relative to a non-inhibitory control molecule tested under identical or substantially identical experimental conditions.
  • a TTSP e.g ., TMPRSS2
  • the TTSP inhibitor is an anti-TMPRSS2 antibody or antigen-binding fragment thereof that inhibits the protease activity of TMPRSS2 but does not substantially inhibit the protease activity of any other TTSP.
  • an anti-TMPRSS2 antibody does not "substantially inhibit the protease activity of any other TTSP" if the antibody, when mixed with TMPRSS4 or HAT, has no effect on the proteolytic activity of TMPRSS4 or HAT, or reduces the proteolytic activity of TMPRSS4 or HAT by no more than 25% ( e.g., by 20%, 15%, 10%, 5%, or less) relative to a non-inhibitory control molecule tested under identical or substantially identical experimental conditions.
  • the TTSP inhibitor is a TMPRSS2 inhibitor
  • the TMPRSS2 inhibitor is the only TTSP inhibitor administered to the subject.
  • the administration of any other TTSP inhibitor e.g ., a TMPRSS4 inhibitor or a HAT inhibitor
  • any other TTSP inhibitor e.g ., a TMPRSS4 inhibitor or a HAT inhibitor
  • an anti-TMPRSS2 inhibitor is specifically excluded.
  • the TTSP inhibitor used in the context of the methods of the present invention can be an antibody or antigen-binding fragment thereof (e.g ., an antibody or antigen-binding fragment thereof that specifically binds TMPRSS2).
  • antibody means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen ( e . g ., TMPRSS2).
  • antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g ., IgM).
  • Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, C H 1, C H 2 and C H 3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region.
  • the light chain constant region comprises one domain (C L 1).
  • V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the anti-TMPRSS2 antibody may be identical to the human germline sequences, or may be naturally or artificially modified.
  • An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
  • antibody also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding portion of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g ., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g ., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
  • CDR complementarity determining region
  • engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.
  • SMIPs small modular immunopharmaceuticals
  • an antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the V H and V L domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain V H -V H , V H -V L or V L -V L dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric V H or V L domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1 ; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L
  • variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
  • a hinge region may consist of at least 2 ( e . g ., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
  • an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V H or V L domain ( e.g ., by disulfide bond(s)).
  • antigen-binding fragments may be monospecific or multispecific (e . g ., bispecific).
  • a multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
  • Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo ), for example in the CDRs and in particular CDR3.
  • the term "human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see , e . g ., Taylor et al., Nucl. Acids Res. 20:6287-6295 (1992 )) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond.
  • the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody).
  • the frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody.
  • a single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form ( Angal et at. (1993) Molecular Immunology 30:105 ) to levels typically observed using a human IgG1 hinge.
  • the instant invention encompasses antibodies having one or more mutations in the hinge, C H 2 or C H 3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.
  • an “isolated antibody,” as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment.
  • an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced is an “isolated antibody” for purposes of the present invention.
  • An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • the present invention includes methods which comprise administering a TTSP inhibitor (e.g., an anti-TMPRSS2 antibody) to a subject, wherein the TTSP inhibitor is contained within a pharmaceutical composition.
  • a TTSP inhibitor e.g., an anti-TMPRSS2 antibody
  • the pharmaceutical compositions of the invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
  • suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
  • a multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA .
  • formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311 .
  • compositions of the invention e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432 ).
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • infusion or bolus injection by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • epithelial or mucocutaneous linings e.g., oral mucosa, rectal and intestinal mucosa, etc.
  • a pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe.
  • a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention.
  • Such a pen delivery device can be reusable or disposable.
  • a reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused.
  • a disposable pen delivery device there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
  • the pharmaceutical composition can be delivered in a controlled release system.
  • a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201 ).
  • polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida .
  • a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533 .
  • the injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
  • aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glycol
  • a nonionic surfactant e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil
  • oily medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
  • dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
  • the amount of TTSP inhibitor (e.g ., anti-TMPRSS2 antibody) administered to a subject according to the methods of the present invention is, generally, a therapeutically effective amount.
  • TTSP inhibitor e.g ., anti-TMPRSS2 antibody
  • the phrase "therapeutically effective amount” means a dose of TTSP inhibitor that results in a detectable improvement in one or more symptoms or biological consequences of influenza virus infection, as that expression is defined herein.
  • various animal models can be used to establish whether a particular amount of a candidate TTSP inhibitor is a therapeutically effective amount.
  • a "therapeutically effective amount" of a TTSP inhibitor also includes a quantity of TTSP inhibitor ( e .
  • TTSP proteolytic activity of the TTSP (e . g ., the ability to cleave HA0 into HA1 and HA2 subunits) by at least 25% relative to a non-inhibitor control molecule tested under identical or substantially identical experimental conditions.
  • a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440
  • the amount of anti-TMPRSS2 antibody contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e ., mg/kg).
  • the anti-TMPRSS2 antibody may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of patient body weight.
  • the methods of the present invention may comprise administering a pharmaceutical composition comprising a TTSP inhibitor (e.g., an anti-TMPRSS2 antibody) to a subject in combination with a second therapeutic agent.
  • a TTSP inhibitor e.g., an anti-TMPRSS2 antibody
  • the phrase "in combination with a second therapeutic agent” means that the second therapeutic agent is administered to the subject before ( e.g., about 1 to 72 hours prior to), after ( e.g., about 1 to 72 hours following), or concurrent with ( e.g., within about 1 hour of) administration of the pharmaceutical composition comprising the TTSP inhibitor to the subject.
  • the second therapeutic agent can be any therapeutic agent that is useful for the treatment or prevention of influenza virus infection on its own.
  • second therapeutic agents that may be administered in combination with a pharmaceutical composition comprising a TTSP inhibitor include, e.g ., amantadine, rimantadine, oseltamivir, zanamivir, aprotinin, leupeptin, cationic steroid antimicrobials ( see, e.g ., US 2007/0191322 ), an influenza vaccine (e.g ., killed, live, attenuated whole virus or subunit vaccine), or an antibody against influenza virus (e.g ., an anti-hemagglutinin antibody).
  • an influenza vaccine e.g ., killed, live, attenuated whole virus or subunit vaccine
  • an antibody against influenza virus e.g ., an anti-hemagglutinin antibody
  • multiple doses of a pharmaceutical composition comprising a TTSP inhibitor may be administered to a subject over a defined time course.
  • the methods according to this aspect of the invention comprise sequentially administering to a subject multiple doses of a TTSP inhibitor.
  • sequentially administering means that each dose of TTSP inhibitor is administered to the subject at a different point in time, e.g ., on different days separated by a predetermined interval (e . g ., hours, days, weeks or months).
  • the present invention includes methods which comprise sequentially administering to the patient a single initial dose of a TTSP inhibitor, followed by one or more secondary doses of the TTSP inhibitor, and optionally followed by one or more tertiary doses of the TTSP inhibitor.
  • the terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the TTSP inhibitor.
  • the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”);
  • the “secondary doses” are the doses which are administered after the initial dose;
  • the “tertiary doses” are the doses which are administered after the secondary doses.
  • the initial, secondary, and tertiary doses may all contain the same amount of TTSP inhibitor, but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of TTSP inhibitor contained in the initial, secondary and/or tertiary doses will vary from one another ( e . g ., adjusted up or down as appropriate) during the course of treatment.
  • each secondary and/or tertiary dose is administered 1 to 30 (e . g ., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) days after the immediately preceding dose.
  • the phrase "the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of TTSP inhibitor which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
  • the methods according to this aspect of the invention may comprise administering to a patient any number of secondary and/or tertiary doses of a TTSP inhibitor.
  • a TTSP inhibitor may comprise administering to a patient any number of secondary and/or tertiary doses of a TTSP inhibitor.
  • only a single secondary dose is administered to the patient.
  • two or more ( e . g ., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
  • only a single tertiary dose is administered to the patient.
  • two or more ( e . g ., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
  • each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 29 days after the immediately preceding dose.
  • each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 1 to 60 days after the immediately preceding dose.
  • the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician or health care provider depending on the needs of the individual patient following clinical examination.
  • any of the foregoing administration regiments may include the administration of one or more additional therapeutic agents in combination with the TTSP inhibitor, as defined elsewhere herein.
  • Example 1 TMPRSS2 Knock-Out Mice Exhibit Improved Survival And Weight Maintenance Compared to Wild-Type Mice Following Influenza A Virus Infection
  • TMPRSS2-KO mice engineered knock-out mice which fail to express a functional TMPRSS2 protein
  • Wild-type littermate mice (“WT”) were used as controls.
  • WT Wild-type littermate mice
  • Trial 1 - Trial 4 Four separate trials (Trial 1 - Trial 4) were carried out in which TMPRSS2-KO mice and WT controls were infected with 10 x MLD 50 (750 PFUs) of A/Puerto Rico/8/1934 H1N1 virus intranasally. Mice were weighed approximately each day after infection and monitored for survival. Euthanasia of infected mice occurred when the animals lost 25% or more of the initial body weight as determined at the time of infection ( e . g ., day 0).
  • mice were also monitored for other overt signs of morbidity, including hunched posture, piloerection, and/or neurological symptoms such as hind-limb paralysis. Results of Trials 1 - 4 are shown in Figures 1 - 4 , respectively. Survival data from the individual Trials is summarized in Table 1. Table 1. Summary of Influenza Infection Trials TRIAL 1 TRIAL 2 TRIAL 3 TRIAL 4 WT KO WO KO WT KO WT KO # Mice 10 10 19 16 30 32 6 15 % Survival 20 100 31 100 36 100 50 100
  • TMPRSS2-KO mice exhibited 100% survival throughout the entire experimental period compared with 20-50% survival for the WT mice.
  • Example 2 TMPRSS2 Knock-Out Mice Exhibit Reduced Viral Burden in the Lungs Compared to Wild-Type Mice Following Influenza A Virus Infection
  • mice and 5 WT controls were infected with 750 PFUs of A/Puerto Rico/8/1934 H1N1 virus intranasally.
  • Five uninfected wild-type and five uninfected TMPRSS2-KO mice were also included in the analyses. Mice were analyzed for: (1) weight change, (2) cellular changes via flow cytometry, (3) immunohistochemistry, PAS and H&E staining of whole lungs, and (4) cytokine levels in serum.
  • TMPRSS2-KO mice infected with influenza A virus (“KO infected") exhibited a 2.2 - 3.4% gain in starting weight, which was only slightly less than the weight gain that was observed in uninfected TMPRSS2-KO mice (5.9 - 6.4% gain) and uninfected WT mice (4.0 - 4.8% gain).
  • Infected WT mice on the other hand, exhibited significant weight loss (11.0 - 11.4% loss) by day 5 post-infection.
  • Fully human anti-TMPRSS2 antibodies are obtained using known methods. The antibodies are tested for the ability to bind cell surface-expressed TMPRSS2. The antibodies may also be tested for the ability to bind soluble versions of TMPRSS2. Antibodies are also tested for the ability to inhibit the proteolytic activity of TMPRSS2 using standard assay formats. For example, the ability of anti-TMPRSS2 antibodies to inhibit TMPRSS2-mediated cleavage of hemagglutinin protein is assayed.
  • Anti-TMPRSS2 antibodies with high affinity binding to TMPRSS2 and the ability to potently inhibit the proteolytic activity of TMPRSS2 are then tested in an in vitro influenza inhibition assay using human bronchial epithelial cells (Calu-3) that express TMPRSS2 (but not human airway trypsin-like protease [HAT]). It is expected that antibodies that interfere with the catalytic function of TMPRSS2 will inhibit viral propagation in this assay.
  • Anti-TMPRSS2 antibodies are tested for their ability to prevent the effects of influenza virus infection using appropriate animal models. Antibodies that block the proteolytic activity of TMPRSS2 are administered to animals prior to experimental influenza virus infection. Control animals are treated with an isotype-matched control antibody prior to infection. It is expected that the animals that are treated with the anti-TMPRSS2 blocking antibodies will exhibit fewer and/or less severe symptoms of influenza virus infection, and/or improved viability, as compared to control treated antibodies.
  • Anti-TMPRSS2 antibodies are also tested for their ability to treat animals that are already infected with influenza virus. Antibodies that block the proteolytic activity of TMPRSS2 are administered to animals after experimental influenza virus infection. Control animals are treated with an isotype-matched control antibody after infection. It is expected that the animals that are treated with the anti-TMPRSS2 blocking antibodies will exhibit fewer and/or less severe symptoms of influenza virus infection, and/or improved viability, as compared to animals treated with control antibodies.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
EP19155349.4A 2012-04-16 2013-04-15 Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers Withdrawn EP3536342A1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201261624519P 2012-04-16 2012-04-16
US201361759469P 2013-02-01 2013-02-01
PCT/US2013/036522 WO2013158516A1 (en) 2012-04-16 2013-04-15 Methods for treating or preventing influenza virus infection by administering a serine protease inhibitor
EP13718744.9A EP2838558A1 (de) 2012-04-16 2013-04-15 Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP13718744.9A Division EP2838558A1 (de) 2012-04-16 2013-04-15 Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers

Publications (1)

Publication Number Publication Date
EP3536342A1 true EP3536342A1 (de) 2019-09-11

Family

ID=48184523

Family Applications (2)

Application Number Title Priority Date Filing Date
EP13718744.9A Ceased EP2838558A1 (de) 2012-04-16 2013-04-15 Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers
EP19155349.4A Withdrawn EP3536342A1 (de) 2012-04-16 2013-04-15 Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP13718744.9A Ceased EP2838558A1 (de) 2012-04-16 2013-04-15 Verfahren zur behandlung oder prävention einer influenzavirusinfektion durch verabreichung eines serinproteasehemmers

Country Status (14)

Country Link
US (1) US9498529B2 (de)
EP (2) EP2838558A1 (de)
JP (2) JP6446355B2 (de)
KR (1) KR20150008383A (de)
CN (1) CN104244978A (de)
AU (2) AU2013249577A1 (de)
BR (1) BR112014025339A8 (de)
CA (2) CA2869010A1 (de)
HK (1) HK1202817A1 (de)
MX (1) MX2014012285A (de)
NZ (1) NZ631105A (de)
SG (1) SG11201405163RA (de)
WO (1) WO2013158516A1 (de)
ZA (1) ZA201406194B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3964207A1 (de) 2020-09-02 2022-03-09 Christian-Albrechts-Universität zu Kiel Antivirale pharmazeutische zusammensetzung zur topischen verabreichung

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10070632B2 (en) * 2016-02-29 2018-09-11 Regeneron Pharmaceuticals, Inc. Rodents having a humanized TMPRSS gene
KR101693243B1 (ko) * 2016-06-15 2017-01-05 재단법인 한국파스퇴르연구소 인플루엔자 바이러스의 복제에 관여하는 신규 인간 유전자 및 이의 용도
MD3638698T2 (ro) * 2018-01-26 2021-07-31 Regeneron Pharma Anticorpi anti-TMPRSS2 și fragmente de legare al antigenului
EP4103619A1 (de) 2020-02-10 2022-12-21 Regeneron Pharmaceuticals, Inc. Anti-tmprss2-antikörper und antigenbindende fragmente
WO2021190980A1 (en) 2020-03-22 2021-09-30 Quadrucept Bio Limited Multimers for viral strain evolution
WO2021195119A1 (en) * 2020-03-24 2021-09-30 Corcept Therapeutics Incorporated Methods of reducing the risk of, severity of, and treating coronavirus infections
WO2022184659A1 (en) 2021-03-01 2022-09-09 Quadrucept Bio Limited Antibody domains & multimers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070191322A1 (en) 2006-02-01 2007-08-16 Savage Paul B Cationic Steroid Microbial Compositions and Methods of Use
JP2008247864A (ja) * 2007-03-30 2008-10-16 Univ Of Tokushima モザイクセリンプロテアーゼ、ｍｓｐとその用途
JP2008308438A (ja) * 2007-06-14 2008-12-25 Mitsubishi Tanabe Pharma Corp 新規なインフルエンザ治療および／または予防薬

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000605A1 (en) * 1998-06-29 2000-01-06 Myriad Genetics, Inc. Tmprss2 is a tumor suppressor
WO2004097358A2 (en) 2003-05-02 2004-11-11 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with human transmembrane serine protease 2 (tmprss2)
EP1846452B1 (de) * 2005-01-07 2014-08-06 Lexicon Pharmaceuticals, Inc. Monoklonale antikörper gegen angiopoietinähnliches protein 4 (angptl4)
BRPI1014745B1 (pt) 2009-06-22 2020-10-20 Borealis Ag artigo para interior de automóveis com odor reduzido
PL3702374T3 (pl) * 2012-02-15 2022-11-21 Cydex Pharmaceuticals, Inc. Sposób wytwarzania pochodnych cyklodekstryny

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070191322A1 (en) 2006-02-01 2007-08-16 Savage Paul B Cationic Steroid Microbial Compositions and Methods of Use
JP2008247864A (ja) * 2007-03-30 2008-10-16 Univ Of Tokushima モザイクセリンプロテアーゼ、ｍｓｐとその用途
JP2008308438A (ja) * 2007-06-14 2008-12-25 Mitsubishi Tanabe Pharma Corp 新規なインフルエンザ治療および／または予防薬

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
"Medical Applications of Controlled Release", 1974, CRC PRES.
ANGAL, MOLECULAR IMMUNOLOGY, vol. 30, 1993, pages 105
BAHGAT ET AL., VIROL. J., vol. 8, 2011, pages 27
BAHGAT MAHMOUD M ET AL: "Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection", VIROLOGY JOURNAL, BIOMED CENTRAL, LONDON, GB, vol. 8, no. 1, 20 January 2011 (2011-01-20), pages 27, XP021089802, ISSN: 1743-422X, DOI: 10.1186/1743-422X-8-27 *
BERTRAM ET AL., REV. MED. VIROL., vol. 20, 2010, pages 298 - 310
BOTTCHER E ET AL: "MDCK cells that express proteases TMPRSS2 and HAT provide a cell system to propagate influenza viruses in the absence of trypsin and to study cleavage of HA and its inhibition", VACCINE, ELSEVIER LTD, GB, vol. 27, no. 45, 23 October 2009 (2009-10-23), pages 6324 - 6329, XP026697593, ISSN: 0264-410X, [retrieved on 20091017], DOI: 10.1016/J.VACCINE.2009.03.029 *
BOTTCHER ET AL., J. VIROL., vol. 80, 2006, pages 9896 - 9898
BOTTCHER EVA ET AL: "Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium", JOURNAL OF VIROLOGY, THE AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 80, no. 19, 1 October 2006 (2006-10-01), pages 9896 - 9898, XP002511838, ISSN: 0022-538X, DOI: 10.1128/JVI.01118-06 *
BOTTCHER-FRIEBERTSHAUSER ET AL., J. VIROL., vol. 85, 2011, pages 1554 - 1562
E. BOTTCHER-FRIEBERTSHAUSER ET AL: "Cleavage of Influenza Virus Hemagglutinin by Airway Proteases TMPRSS2 and HAT Differs in Subcellular Localization and Susceptibility to Protease Inhibitors", JOURNAL OF VIROLOGY, vol. 84, no. 11, 1 June 2010 (2010-06-01), pages 5605 - 5614, XP055064923, ISSN: 0022-538X, DOI: 10.1128/JVI.00140-10 *
E. BOTTCHER-FRIEBERTSHAUSER ET AL: "Inhibition of Influenza Virus Infection in Human Airway Cell Cultures by an Antisense Peptide-Conjugated Morpholino Oligomer Targeting the Hemagglutinin-Activating Protease TMPRSS2", JOURNAL OF VIROLOGY, vol. 85, no. 4, 15 February 2011 (2011-02-15), pages 1554 - 1562, XP055064795, ISSN: 0022-538X, DOI: 10.1128/JVI.01294-10 *
GOODSON, MEDICAL APPLICATIONS OF CONTROLLED RELEASE, vol. 2, 1984, pages 115 - 138
GOVORKOVA ELENA A ET AL: "Combination chemotherapy for influenza.", VIRUSES AUG 2010, vol. 2, no. 8, August 2010 (2010-08-01), pages 1510 - 1529, XP002698067, ISSN: 1999-4915 *
HIROSHI KIDO ET AL: "Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - PROTEINS & PROTEOMICS, ELSEVIER, NETHERLANDS, vol. 1824, no. 1, 5 July 2011 (2011-07-05), pages 186 - 194, XP028336056, ISSN: 1570-9639, [retrieved on 20110723], DOI: 10.1016/J.BBAPAP.2011.07.001 *
JUSTIN D. HOOPES ET AL: "Triple Combination Antiviral Drug (TCAD) Composed of Amantadine, Oseltamivir, and Ribavirin Impedes the Selection of Drug-Resistant Influenza A Virus", PLOS ONE, vol. 6, no. 12, 29 December 2011 (2011-12-29), pages e29778, XP055064928, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0029778 *
LANGER, SCIENCE, vol. 249, 1990, pages 1527 - 1533
POWELL ET AL.: "Compendium of excipients for parenteral formulations", J PHARM SCI TECHNOL, vol. 52, 1998, pages 238 - 311, XP009119027
REMINGTON: "Pharmaceutical Sciences", MACK PUBLISHING COMPANY
SEFTON, CRC CRIT. REF. BIOMED. ENG., vol. 14, 1987, pages 201
SZABO R ET AL: "Type II transmembrane serine proteases in development and disease", INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, PERGAMON, GB, vol. 40, no. 6-7, 1 June 2008 (2008-06-01), pages 1297 - 1316, XP022655973, ISSN: 1357-2725, [retrieved on 20071204], DOI: 10.1016/J.BIOCEL.2007.11.013 *
TAYLOR ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 6287 - 6295
WU ET AL., J. BIOL. CHEM., vol. 262, 1987, pages 4429 - 4432

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3964207A1 (de) 2020-09-02 2022-03-09 Christian-Albrechts-Universität zu Kiel Antivirale pharmazeutische zusammensetzung zur topischen verabreichung
WO2022049177A1 (en) 2020-09-02 2022-03-10 Christian-Albrechts-Universität Zu Kiel Antiviral pharmaceutical composition for topical administration

Also Published As

Publication number Publication date
BR112014025339A2 (pt) 2013-10-24
MX2014012285A (es) 2015-04-13
BR112014025339A8 (pt) 2018-01-16
JP2018048169A (ja) 2018-03-29
AU2013249577A1 (en) 2014-10-02
KR20150008383A (ko) 2015-01-22
NZ631105A (en) 2016-09-30
CA3219083A1 (en) 2013-10-24
ZA201406194B (en) 2016-08-31
HK1202817A1 (en) 2015-10-09
US9498529B2 (en) 2016-11-22
EP2838558A1 (de) 2015-02-25
WO2013158516A1 (en) 2013-10-24
JP6446355B2 (ja) 2018-12-26
AU2018200265A1 (en) 2018-02-01
AU2018200265B2 (en) 2019-07-18
SG11201405163RA (en) 2014-09-26
US20130273070A1 (en) 2013-10-17
CA2869010A1 (en) 2013-10-24
JP2015516975A (ja) 2015-06-18
CN104244978A (zh) 2014-12-24

Similar Documents

Publication Publication Date Title
AU2018200265B2 (en) Methods for treating or preventing influenza virus infection by administering a serine protease inhibitor
US11167004B2 (en) Methods for treating severe atopic dermatitis by administering an IL-4R inhibitor
KR102462039B1 (ko) Il-4r 길항제를 투여함에 의해 알레르기를 예방하거나 치료하기 위한 방법
EP3889181B1 (de) Ein il-4r-antagonistischer antikörper zur verwendung in der behandlung atopischer dermatitis
EP3515465B1 (de) Verfahren zur behandlung schwerer atopischer dermatitis durch verabreichung eines il-4r-inhibitors
US20230102151A1 (en) Methods for treating atopic dermatitis by administering an il-4r antagonist
AU2017321682B2 (en) Methods for preventing or treating allergy by administering an IL-4R antagonist
AU2024203951A1 (en) Methods for treating severe atopic dermatitis by administering an IL-4R inhibitor

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED

AC Divisional application: reference to earlier application

Ref document number: 2838558

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200228

RAX Requested extension states of the european patent have changed

Extension state: BA

Payment date: 20200228

Extension state: ME

Payment date: 20200228

RBV Designated contracting states (corrected)

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40014386

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20210129

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20230817